Deficiencies of three purine enzymes have been described which are associated with primary immunodeficiency diseases. Two of these, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are sequential enzymes in the purine salvage pathway. Deficiency of ADA or PNP, however, results in distinct clinical and immunologic pictures. Also, the defects associated with these enzyme deficiencies almost exclusively involve the immune system. These findings indicate that the metabolism of purines is distinct in T and B lymphocytes, and within subpopulations of T lymphocytes. It is also likely that purine metabolism in the immune system changes as a function of ontogeny and differentiation and that these differences account for some of the functional characteristics of T and B lymphocytes and the immunodeficiencies seen in PNP and ADA deficient patients. The specific aims of this research project are: 1) to evaluate the ontogeny and differentiation of human T cell immunity with respect to purine metabolism; 2) to use a model of PNP deficiency in PHA stimulated human peripheral blood lymphocytes to explore the role of PNP for maintaining normal immune function; and 3) to characterize the synthesis of purine to subpopulations of normal human peripheral blood lymphocytes. The long term goal of this program is to develop rational approaches for modulating immune function based upon these biochemical differences. This research program will: 1) provide a better understanding of the biochemical basis of normal immune function; 2) advance our understanding of the disease processes in immunodeficiency disorders; 3) improve the ability to recognize and classify the stage or differentiation of normal and malignant cells on the basis of their biochemistry; and 4) enhance the evaluation of immunosuppressive drugs and development of new pharmacologic agents which are more selective and potent.